The lethal effects of 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic
acid (
cis-acid), a water-soluble nitrosourea derivative, were investigated on a human
lymphoma cell line. The survival of asynchronous cells exposed to increasing concentrations of the
drug was characterized by a threshold exponential curve (Do = 20 microgram/ml; Dq = 20 microgram/ml, 1 hour) similar to that of other nitrosourea derivatives.
cis-Acid exerted its main killing effect on cells in early S and in late G2 phase. Cells in mid S and early G1 phase were tenfold more resistant. Changes in survival response as a function of cell cycle stage were reflected primarily by changes in the extent of the shoulder region of the survival curve. In contrast to other nitrosoureas, the lethal effectiveness of
cis-acid in
solution was stable and the
drug could sterilize large numbers of cells in short periods of time. Another important major difference observed for
cis-acid with respect to classic nitrosourea derivatives was the capacity of treated cells to recover from sublethal and potentially lethal damage. Our studies have shown that
cis-acid is as effective in killing cultured human
lymphoma cells as other nitrosoureas, but possibly with a mechanism different from that of these compounds. The major shortcoming noted for
cis-acid, namely the capacity of treated cells to recover from
drug-induced damage, is offset by the relatively long stability of its killing effect. This, and the fact that
cis-acid can be administered in an aqueous
solution, make this agent an appealing compound for clinical trials.